38 replies to this topic

[CIMN]

I am concerned about high doses of pramiracetam, but i think it has much use at lower doses, it also was used for traumatic brain injuries, you might find mentioned in a abstract.

i understand excessive calcium signaling can become a hazard (though it is also needed in cell survival signaling from what I've read at the least(not excessive i mean), .. is their a specific study/abstract that caused you to be convinced of the calcium danger that you speak about? (can you show where its mentioned of oxiracetam, calcium and stress to cells) is that a conjecture from your mind from inferences from multiple studies unrelated specifically to oxiracetam?

or is it mentioned in a specific science abstract? (i just would like to find the exact reference if you have read one) that caused you to become alarmed.., i appreciate the help, and discussion

Edited by CIMN, 22 August 2012 - 05:45 PM.

[renfr]

I am concerned about high doses of pramiracetam, but i think it has much use at lower doses, it also was used for traumatic brain injuries, you might find mentioned in a abstract.

i understand excessive calcium signaling can become a hazard (though it is also needed in cell survival signaling from what I've read at the least(not excessive i mean), .. is their a specific study/abstract that caused you to be convinced of the calcium danger that you speak about? (can you show where its mentioned of oxiracetam, calcium and stress to cells) is that a conjecture from your mind from inferences from multiple studies unrelated specifically to oxiracetam?

or is it mentioned in a specific science abstract? (i just would like to find the exact reference if you have read one) that caused you to become alarmed.., i appreciate the help, and discussion

Well when there is an excess of glutamate in your system (here the glutamate is potentiated by racetams overall oxiracetam and pramiracetam) your brain cells are unable to metabolize all of it, so the excess stays out of the cells and causes a rise of calcium in glutamate receptor channels (in the membrane of your cells) why infects the cells with calcium overload then the cell gets killed. This is called glutamate excitotoxicity and this is really killer.
That's why if you want to avoid that you should not overdose and you should also supplement a calcium channel blocker such as magnesium.
As for studies I have none in mind right, however a simple search on oxiracetam and glutamatergic activity will certainly gives you results.
Oxiracetam and pramiracetam are really strong glutamate activators, besides pramiracetam is linked to NOS increase. On the other hand, piracetam and aniracetam are positive allosteric modulators, they're unlikely to cause any severe damage.

[CIMN]

I am concerned about high doses of pramiracetam, but i think it has much use at lower doses, it also was used for traumatic brain injuries, you might find mentioned in a abstract.

i understand excessive calcium signaling can become a hazard (though it is also needed in cell survival signaling from what I've read at the least(not excessive i mean), .. is their a specific study/abstract that caused you to be convinced of the calcium danger that you speak about? (can you show where its mentioned of oxiracetam, calcium and stress to cells) is that a conjecture from your mind from inferences from multiple studies unrelated specifically to oxiracetam?

or is it mentioned in a specific science abstract? (i just would like to find the exact reference if you have read one) that caused you to become alarmed.., i appreciate the help, and discussion

Well when there is an excess of glutamate in your system (here the glutamate is potentiated by racetams overall oxiracetam and pramiracetam) your brain cells are unable to metabolize all of it, so the excess stays out of the cells and causes a rise of calcium in glutamate receptor channels (in the membrane of your cells) infects the cells with calcium overload then the cell gets killed. This is called glutamate excitotoxicity and this is really killer.
That's why if you want to avoid that you should not overdose and you should also supplement a calcium channel blocker such as magnesium.
As for studies I have none in mind right, however a simple search on oxiracetam and glutamatergic activity will certainly gives you results.

Oxiracetam and pramiracetam are really strong glutamate activators, besides pramiracetam is linked to NOS increase. On the other hand, piracetam and aniracetam are positive allosteric modulators, they're unlikely to cause any severe damage.

if you can please share whatever references that you have linking the racetams and toxicity, i found a couple in particular. not too specific but it shows calcium channels are involved.
my question is how do you know oxiracetam is such a strong glutamate activator? is it solely because of the effect on calcium channels?



Brain Res. 1990 Aug 20;525(2):319-21.
Calcium entry blockers and oxiracetam have opposite effects on the density of dihydropyridine receptors in rat cerebral cortex.

Dudkin SM, Polev PV, Soldatov NM.

Source

Centre of Medical Biotechnology, Moscow U.S.S.R.

Abstract

Ca2+ entry blockers riodipine, D-cis-diltiazem and verapamil, when administered i.p. to rats at a dose of 10 mg/kg, produced two-fold decreases in the density of 1,4-dihydropyridine (DHP) receptors in rat cerebral cortex, as revealed by Scatchard plot analysis of radioligand binding made 24 h after the first injection. Thereafter, the number of DHP binding sites increased up to the initial level on day 4 of the treatment. The nootropic drugoxiracetam, when injected simultaneously with Ca2+ channel blockers at a dose of 10 mg/kg, prevented this transient decrease in DHP receptor density in brain. These results can explain the opposite modulation of memory retention by calcium antagonists and nootropic drugs that has been observed previously.

PMID: 2174714 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm..../pubmed/2174714
http://www.ncbi.nlm..../pubmed/2177669
http://www.ncbi.nlm....pubmed/10850736



Brain Res Brain Res Rev. 1994 May;19(2):180-222.
Piracetam and other structurally related nootropics.

Source

Department of Chemistry, Aarhus University, Denmark.

Abstract

Nearly three decades have now passed since the discovery of the piracetam-like nootropics,
compounds which exhibit cognition-enhancing properties, but for which no commonly accepted
mechanism of action has been established. This review covers clinical, pharmacokinetic,
biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references)
of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their
structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced
by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is
observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of
dementia has been demonstrated. No affinity for the alpha 1-, alpha 2-, beta-, muscarinic,
5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA)
(except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found.
The racetams possess a very low toxicity and lack serious side effects. Increased turnover
of different neurotransmitters has been observed as well as other biochemical findings, e.g.
, inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has,
however, emerged. We believe that the effect of the racetams is due to a potentiation of already present
neurotransmission and that much ion flux by, e.g., evidence points in the direction of a modulated
potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated
sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated
channels or voltage-dependent channels or decreases in potassium efflux. Effects on
carrier mediated ion transport are also possible.

PMID: 8061686 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm..../pubmed/8061686

Edited by CIMN, 23 August 2012 - 04:31 PM.

[CIMN]

Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders.

Malykh AG, Sadaie MR.

Source

NovoMed Consulting, Silver Spring, Maryland 20904, USA.

Abstract

There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant.The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgroup 1. Based on calculations of the efficacy rates, our assessments indicate notable improvements in clinical outcomes with some of these agents.

PMID: 20166767 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/20166767

Well when there is an excess of glutamate in your system (here the glutamate is potentiated by racetams overall oxiracetam and pramiracetam) your brain cells are unable to metabolize all of it, so the excess stays out of the cells and causes a rise of calcium in glutamate receptor channels

and that excess of glutamate would cause excitotoxic calcium overload right? ..
but thats from glutamate. not the racetams, racetams potentiate the calcium influx though.. but they also work in up and downward fashion from what i have read, they regulate the calcium influx.



The effects of piracetam and its novel peptide analogue GVS-111 on neuronal voltage-gatedcalcium and potassium channels.

Solntseva EI, Bukanova JV, Ostrovskaya RU, Gudasheva TA, Voronina TA, Skrebitsky VG.

Source

Institute of Brain Research, Russian Academy of Medical Sciences, Moscow, Russia. Elena@synaptology.msk.su

Abstract

1. With the use of the two-microelectrode voltage-clamp method, three types of voltage-activated ionic currents were examined in isolated neurons of the snail Helix pomatia: high-threshold Ca2+ current (ICa), high-threshold Ca(2+)-dependent K+ current (IK(Ca)) and high-threshold K+ current independent of Ca2+ (IK(V)). 2. The effect of bath application of the nootropics piracetam and a novel piracetam peptide analog, ethyl ester of N-phenyl-acetyl-L-prolyl-glycine (GVS-111), on these three types of voltage-activated ionic currents was studied. 3. In more than half of the tested cells, ICa was resistant to both piracetam and GVS-111. In the rest of the cells, ICa decreased 19 +/- 7% with 2 mM of piracetam and 39 +/- 14% with 2 microM of GVS-111. 4. IK(V) in almost all cells tested was resistant to piracetam at concentrations up to 2 mM. However, IK(V) in two-thirds of the cells was sensitive to GVS-111, being suppressed 49 +/- 18% with 1 microM GVS-111. 5. IK(Ca) appeared to be the most sensitive current of those studied to both piracetam and GVS-111. Piracetam at 1 mM and GVS-111 at 0.1 microM decreased the amplitude of IK(Ca) in most of the cells examined by 49 +/- 19% and 69 +/- 24%, respectively. 6. The results suggest that piracetam and GVS-111 suppression of voltage-activated calcium and potassium currents of the neuronal membrane may regulate (both up and down) Ca2+ influx into neurons.

Edited by CIMN, 23 August 2012 - 05:14 PM.

[Citrus Bolt]

I've been interested in nebracetam,thanks for that.

i wonder why the other racetam drugs aren't produced as much as the common few seen around, why is that?

Because they're not researched enough. Studies are very scarce and who knows if those racetams are toxic or not whether on short-term or long-term use.
For instance nefiracetam is killer for your testicles and pramiracetam can cause extreme glutamate excitotoxicity and NOS damage at high doses. As for other racetams such as piracetam, aniracetam or oxiracetam they have been more studied and are considered as very safe.
Oxiracetam could be an exception on the long-term as it can cause stress and calcium damage on stressed individuals or at high doses and stress is known to be a factor of cell death.
I guess if you really want to try out those dark racetams, you will probably find a supplier on Alibaba or ask a lab to synthetize the molecule.

Really? If your concerns are as true and dramatic as they sound then you should probably alert the rest of this forum by making a thread and sharing the references to what you have read on that. many people still use oxiracetam and pramiracetam here. can you link to the exact study you are referring to on oxiracetam?

Yes oxiracetam and pramiracetam have reached a certain popularity on this forum but users typically get benefits from their use as the dosages are relatively low.
However, oxiracetam and pramiracetam stll have caused fatalities, the case of 1 user who took 12g of oxiracetam (huuuuuuuuuuuuuge dose) and kept in mind all his chemistry courses for exams and the day of the exams, he happened to have severe cognitive impairement and didn't remember a single thing.
I could also add myself in the fatalities, as I also experienced such effects from doses as low as 2g, this effect is likely due to calcium channel flows that trigger biological stress.
Some people might use high dosages of oxiracetam and experience nothing but benefits, I envy them, but other users might be more sensitive. I never saw someone getting extreme cognitive damage from oxiracetam, it's relatively safe but if you know such dosages trigger biological stress, you'd be careful as this is harmful for your neurons.
A fix to that is obviously lowering intake and possibly supplementing magnesium.

As for pramiracetam, it however caused more serious issues to one user who only took 1000mg, which is over the 100mg dosage recommended by most suppliers but still far away from the human dose supposed NOS damage that is around 5000mg and even more away from users who megadosed up to 11g.
The user was probably one of the harshest fatalities there, total cognitive impairement,his memory became poor and didn't improve and his cognitive skills sharply decreased. So yes again, this is a matter of sensitivity and one should always try low dosage and if needed under RDA to prevent massive damage in case of toxicity issues.

Last but not least, even some report that piracetam was harmful to them, you can look at Nootropix from Thailand who claims to have suffered damage from piracetam use, I don't know which dosage he did use but piracetam is like most of racetams a double faced molecule, for some they get depressed when using it, for others it relieves their mood. For Nootropix it makes him depressed, as for me it rather uplifts my mood.

Of course I can't check for veracity of user claims and tell you if what they say is true, however I and many other users read their posts and I find them enough serious to think it did happen.
There are probably people there who wants to get rid of racetams and disprove them, those liars such as the nootropic rookie who claim taking ultra mega dosages and then get brain lesions. First of all it's not surprising at all that those crazy dosages cause damage and second if it did cause damage that fool wouldn't use the same mega dosage for months straight.

I'm sorry, but you keep using the word 'fatality'. That's not actually what you mean though, right? I'm assuming these people didn't die, because you list yourself as one of them.

[CIMN]

so i guess the questsion to ask is, do the racetams cause toxicity? can they potentiate it? or do they reduce it?

I think i have to learn more about what up and downward regulation means regarding calcium channel influx.

i thank you for providing your thoughts on possible calcium dangers renfr, i think we need just a bit more research and things should get much more clear. pretty crazy how there seems to be so many opposing statements in racetam research, calcium channels may be key to understanding that.

What are your thoughts on " up and downward " regulation of calcium channels? what are the implications of that ?

Edited by CIMN, 23 August 2012 - 11:16 PM.

[CIMN]

link to other thread
http://www.longecity...not-neurotoxic/

[Isochroma]

For those that want to try the obscure Racetams - Coluracetam, Sunifiram and Unifiram - today's a special day

As of this day I have received an email from Season [TrustWe Group]: Finally a trustable supplier of these obscure Racetams who takes PayPal - hover your mouse over the PP link on the Payment column to see her PayPal address on the actual page - with product in stock [Sunifiram] and shortly [Coluraceam, Unifiram] in stock with prices that are cheap enough for everyone to afford!

The newly-released Racetams are: Phenylpiracetam, Sunifiram, Unifiram and Coluracetam with prices that are revolutionarily affordable - with assurance of superfast delivery by fully-trackable EMS [Express Mail Service] and money-back guarantee by PayPal!

Phenylpiracetam is IN STOCK NOW FOR IMMEDIATE SHIPMENT.
Coluracetam will be in stock halfway through April 2013. [DARK PURPLE COLORED TEXT IN TABLES INDICATES FUTURE STOCK]
Sunifiram is IN STOCK NOW FOR IMMEDIATE SHIPMENT.
Unifiram will be in stock halfway through April 2013. [DARK PURPLE COLORED TEXT IN TABLES INDICATES FUTURE STOCK]

Here are the new additions to the Racetam Prices list, including the first seller for the entirely new category of Raceram: Unifiram.

Below is just an image of the new additions - this forum will not allow proper insertion of the entries without mangling them.
The actual text and links are on the page itself so please go there to find out more - click the table below for details:



Coluracetam is a highly active and very potent nootropic with doses of 10mg (typical) as found by forum members from ScienceGuy's test samples.

Sunifiram and Unifiram are extremely potent nootropics with doses of about 5mg per 150lbs.

The racetam titles at the top of each table are linked to their respective Wikipedia entries. Click to find out more about them

[Isochroma]

As of today [Version March 24.1 2013] a new and very affordable Sunifiram vendor has been added to the Racetam Prices list - New Star Nootropics - a reseller who can ship by regular mail or Express Mail.

Prices for both shipping modes have been calculated for all sizes of product for better cost comparison.

Edited by Isochroma-Reborn, 24 March 2013 - 09:17 PM.